Control of Synaptic Strength by Glial TNFα

Beattie, Eric C.; Stellwagen, David; Morishita, Wade; Bresnahan, Jacqueline C.; Ha, Byeong Keun; Zastrow, Mark von; Beattie, Michael S.; Malenka, Robert C.

doi:10.1126/science.1067859

Cited by 1,218 publications

(914 citation statements)

References 22 publications

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“…Motor neurons are known to be especially vulnerable to AMPA‐mediated excitotoxicity due to an unusually high density of Ca 2+ ‐permeable AMPA receptors and low calcium buffering ability (Palecek, Lips, & Keller, 1999; Vandenberghe et al 2000). Furthermore, neighboring astrocytes are known to be key regulators of these AMPA receptors (Beattie, 2002; Van Damme et al, 2007). Here, we show that the AMPAR GluA2 subunits are decreased, while GluA1 subunits are increased in the dendrites of motor neurons exposed to mutFUS ACM but not WTFUS ACM.…”

Section: Discussionmentioning

confidence: 99%

Astrocytes expressing ALS‐linked mutant FUS induce motor neuron death through release of tumor necrosis factor‐alpha

Kia

McAvoy

Krishnamurthy

et al. 2018

Glia

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Mutations in fused in sarcoma (FUS) are linked to amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease affecting both upper and lower motor neurons. While it is established that astrocytes contribute to the death of motor neurons in ALS, the specific contribution of mutant FUS (mutFUS) through astrocytes has not yet been studied. Here, we used primary astrocytes expressing a N‐terminally GFP tagged R521G mutant or wild‐type FUS (WTFUS) and show that mutFUS‐expressing astrocytes undergo astrogliosis, damage co‐cultured motor neurons via activation of an inflammatory response and produce conditioned medium (ACM) that is toxic to motor neurons in isolation. Time lapse imaging shows that motor neuron cultures exposed to mutFUS ACM, but not WTFUS ACM, undergo significant cell loss, which is preceded by progressive degeneration of neurites. We found that Tumor Necrosis Factor‐Alpha (TNFα) is secreted into ACM of mutFUS‐expressing astrocytes. Accordingly, mutFUS astrocyte‐mediated motor neuron toxicity is blocked by targeting soluble TNFα with neutralizing antibodies. We also found that mutant astrocytes trigger changes to motor neuron AMPA receptors (AMPAR) that render them susceptible to excitotoxicity and AMPAR‐mediated cell death. Our data provide the first evidence of astrocytic involvement in FUS‐ALS, identify TNFα as a mediator of this toxicity, and provide several potential therapeutic targets to protect motor neurons in FUS‐linked ALS.

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Section: Discussionmentioning

confidence: 99%

Astrocytes expressing ALS‐linked mutant FUS induce motor neuron death through release of tumor necrosis factor‐alpha

Kia

McAvoy

Krishnamurthy

et al. 2018

Glia

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“…Activated glial cells contribute to the phagocytosis of degenerating axons. They liberate factors such as TNFa (tumour necrosis factor alpha) which enhances the efficacy of excitatory synapses by increasing surface expression of AMPA receptors (Beattie et al, 2002) and also growth factors and other molecules associated with axonal growth (Deller & Frotscher, 1997). Glial reactions may then promote compensatory sprouting and circuit reorganisation 2000; (Bechmann &Nitsch, 2000;Ide et al, 1996), but on the other hand glial scar tissue can act as a mechanical barrier and liberate glycoproteins and other factors which inhibit axonal growth (Fawcett & Asher, 1999).…”

Section: Does An Epileptic Brain Emerge From Developmental and Repairmentioning

confidence: 99%

Mesial temporal lobe epilepsy: A pathological replay of developmental mechanisms?

Cohen

Navarro

Duigou

et al. 2003

Biology of the Cell

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“…As recently reviewed, immunopathological findings are common in individuals with schizophrenia who sometimes show signs of infectious factors and a certain degree of nonspecific inflammatory reactions that are consistent with a possible role of TNFA dysfunction in disease etiology through an infection or inflammatory mechanism. 26 Recent research indicates the possible role of glial TNFA and other cytokines in synaptic strength control at excitatory synapses 70 and apoptosis of oligodendrocytes through glutamate excitotoxicity. 71 This provides a different kind of mechanistic link to schizophrenia that would be compatible with the increasing genetic evidence for the glutamate hypothesis.…”

Section: Discussionmentioning

confidence: 99%

Tumor necrosis factor promoter haplotype associated with schizophrenia reveals a linked locus on 1q44

et al. 2004

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Using restriction fragment length polymorphism and pyrosequencing methods, we genotyped two TNFA gene promoter SNPs (ÀG308A, ÀG238A) and analyzed the haplotype structure in 24 Canadian families of primarily Celtic origin. Our results demonstrate that after correction for multiple testing based on simulations of 10 000 replicates of unlinked/unassociated data, there is evidence for association (P ¼ 0.026) of a specific haplotype (À308A, À238G) with schizophrenia and schizophrenia spectrum disorders with a family-based trimmed haplotype linkage disequilibrium test (Trimhap). Stratifying the 22 families with genome scan data by TNFA promoter haplotypes followed by reanalysis of linkage to schizophrenia throughout the genome, we identified few loci that exhibit a considerable increase in LOD/HLOD scores. A locus on chromosome 1q44 (D1S1609) demonstrated a significant increase (P ¼ 0.025) in LOD score from 0.15 to 3.01 with a broad definition of the schizophrenia phenotype and a dominant mode of inheritance. This result replicates a previously reported positive result of linkage of schizophrenia spectrum disorders to this area of the genome. We also illustrated that simulation studies are pivotal in evaluating the significance of results obtained with newer statistical methods, when multiple, but not independent, tests are performed, and when sample stratification is utilized to reduce the impact of heterogeneity or assess the interaction between loci.

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Control of Synaptic Strength by Glial TNFα

Cited by 1,218 publications

References 22 publications

Astrocytes expressing ALS‐linked mutant FUS induce motor neuron death through release of tumor necrosis factor‐alpha

Astrocytes expressing ALS‐linked mutant FUS induce motor neuron death through release of tumor necrosis factor‐alpha

Mesial temporal lobe epilepsy: A pathological replay of developmental mechanisms?

Tumor necrosis factor promoter haplotype associated with schizophrenia reveals a linked locus on 1q44

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